Cytochrome P-450 pathway in acetylcholine-induced canine coronary microvascular vasodilation in vivo.
In the canine coronary microcirculation, acetylcholine (ACh)-induced vasodilation of large (> or = 100 microns) epicardial arterioles (LgA), but not small (< 100 microns) epicardial arterioles (SmA), is blocked by nitric oxide (NO) synthase inhibitors in vivo. We hypothesized that the ACh-induced vasodilation of SmA is mediated by a cytochrome P-450 metabolite of arachidonic acid (AA). Epicardial coronary microvascular diameters in dogs were measured at baseline and after treatment with topically applied ACh (1, 10, and 100 microM), AA (1, 5, and 10 microM), or sodium nitroprusside (SNP; 10-100 microM). Coronary microvascular diameters were compared among control dogs (group OO); dogs pretreated with N omega-nitro-L-arginine (L-NNA; 70 microM topically) (group NO); dogs pretreated with L-NNA plus clotrimazole (Clo; 1.6 microM topically) or 17-octadecynoic acid (ODYA; 2 microM topically), cytochrome P-450 monooxygenase inhibitors (groups NC and NY, respectively); dogs pretreated with Clo alone (group OC); and dogs pretreated with L-NNA plus Clo with AA as the agonist (group AA). ACh-induced vasodilation of LgA was abolished by L-NNA alone, whereas in SmA, L-NNA was without effect. Clo alone did not inhibit ACh-induced dilation in either SmA or LgA. However, the combinations of L-NNA plus either Clo or ODYA abolished ACh- and AA-induced dilation of SmA (100 microM ACh: NC, 3 +/- 5%; NY, 8 +/- 2%; 10 microM AA: 6 +/- 3%) but did not affect responses to SNP. These results suggest that the ACh-induced vasodilation of SmA is mediated in part by cytochrome P-450 metabolites of AA and provide the first evidence that the cytochrome P-450 pathway contributes to the regulation of coronary resistance vessels in vivo.
Widmann
M D
MD
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, USA.
Weintraub
N L
NL
Fudge
J L
JL
Brooks
L A
LA
Dellsperger
K C
KC
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001160:Arterioles / Q000187:drug effects / Q000502:physiology*; D003022:Clotrimazole / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005260:Female; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D019335:Nitroarginine / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D016277:Ventricular Function, Left
D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D009599:Nitroprusside; D019335:Nitroarginine; D016718:Arachidonic Acid; C047008:17-octadecynoic acid; D003577:Cytochrome P-450 Enzyme System; D003022:Clotrimazole; D000109:Acetylcholine